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Principal Investigator: Priya Shirish Shah
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $548,496
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Viruses that infect the developing brain, including Zika virus (ZIKV), cytomegalovirus, and rubella virus cause
major birth defects. Microcephaly is one such birth defect, in which head and brain size are severely reduced,
and is often accompanied by intellectual disability. This virally-inflicted neurological disease, or viral
neuropathogenesis, can be caused by multiple mechanisms. One recently identified way ZIKV non-structural
protein 4A (NS4A) causes microcephaly is by disrupting the human ANKLE2 protein. Interestingly, individuals
with mutations in the gene encoding ANKLE2 suffer from microcephaly. ANKLE2 is conserved from worms to
humans, and is essential for coordinating cell division during brain development. ANKLE2 derives this function
in cell division and development by mediating protein interactions. NS4A physically interacts with ANKLE2 and
disrupts brain development in an ANKLE2-dependent manner in a fruit fly model of brain development. ANKLE2
also promotes ZIKV replication. Taken together, these studies show that in the process of coopting a host protein
for replication, ZIKV dysregulates an important developmental pathway. Thus, the NS4A-ANKLE2 protein
interaction represents an important model to study viral neuropathogenesis and how it is connected to viral
replication and hereditary disorders at the molecular level.
The long-term goal of this work is to decipher how virus-host protein interactions impact virus replication and
pathogenesis, as these discoveries will fuel therapeutic target identification and drug development. The
objective of this proposal is to dissect the mechanisms by which the protein interaction between ZIKV NS4A
and human ANKLE2 promote ZIKV replication and inhibit brain development. To accomplish this objective, we
will test the central hypothesis that ANKLE2 promotes viral replication through its interaction with NS4A and
by recruiting other host factors involved in ZIKV replication to sites of replication, and this disrupts physiological
ANKLE2 protein interactions required for brain development. The following specific aims will test this hypothesis:
Aim 1: Dissect the impact of the NS4A-ANKLE2 protein interaction in ZIKV replication and pathogenesis.
Aim 2: Unravel the molecular function of ANKLE2 in ZIKV replication and pathogenesis.
When completed, this work will delineate how a single virus-host protein interaction rewires a developmental
pathway to facilitate virus replication and inflict neurological disease at the molecular level. This will reveal
detailed biochemical insight into a virus-host protein interaction with amino acid-level resolution, new host factors
that play a role in ZIKV replication, and previously unknown proteins key to brain development and disrupted in
other hereditary developmental disorders. In the long term, the methods established here could be employed to
uncover the molecular mechanisms behind other diseases with viral and hereditary etiologies.
Terms: <Alleles><Allelomorphs><Amino Acids><Assay><Bioassay><Biochemical><Biological Assay><Birth Defects><Brain><Brain Nervous System><CMV><Causality><Cell division><Chemicals><Collaborations><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytomegalovirus><Development><Disease><Disorder><Drosophila><Drosophila genus><Encephalon><Etiology><Fetal Tissues><Future><Genes><Genetic Alteration><Genetic Change><Genetic Determinism><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic defect><Genetic propensity><Genetics-Mutagenesis><German Measles Virus><Goals><HCMV><Head><Hereditary><Hereditary Disease><Host Factor><Host Factor Protein><Human><In Vitro><Inborn Genetic Diseases><Individual><Infection><Inherited><Inherited Predisposition><Inherited Susceptibility><Inherited disorder><Integration Host Factors><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Link><M Phase><Mediating><Methods><Mice><Mice Mammals><Microcephaly><Mitosis><Mitosis Stage><Modeling><Modern Man><Molecular><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Nervous System Diseases><Nervous System Disorder><Neural Stem Cell><Neurologic Disorders><Neurological Disorders><Neuropathogenesis><Non-structural Protein><Nonstructural Protein><Pathogenesis><Pathogenicity><Pathway interactions><Phenotype><Phosphorylation><Physiologic><Physiological><Process><Protein Phosphorylation><Proteins><Proteomics><Publishing><Replication Process><Replication-Associated Process><Reporter><Resolution><Role><Rubella virus><Salivary Gland Viruses><Scaffolding Protein><Site><System><Testing><Transgenic Organisms><Variant><Variation><Viral><Viral Pathogenesis><Virus><Virus Replication><Work><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><Zika Virus><Zika virus infection><aminoacid><brain size><causation><cytomegalovirus group><developmental><developmental disease><developmental disorder><disease causation><drug development><experiment><experimental research><experimental study><experiments><fetus tissue><fruit fly><genetic determinant><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome mutation><hereditary disorder><heritable disorder><human pathogen><in vivo><inborn error><infected with ZIKV><infected with zika><inherited diseases><inherited genetic disease><inherited genetic disorder><insight><intellectual and developmental disability><knock-down><knockdown><limited intellectual functioning><micrencephaly><microencephaly><mouse model><murine model><mutant><mutation scanning><mutation screening><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurological disease><neuron progenitors><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><pathway><recruit><resolutions><social role><therapeutic target><transgenic><viral multiplication><viral replication><virus host interaction><virus multiplication><virus pathogenesis><zika infected><zika infection><zika viral infection><zikav>